This invention relates to novel bile acid derivatives and production thereof. These bile acid derivatives are useful as therapeutical drugs for cancers.
Bile acids are one kind of steroid compounds, constituting the main components of bile of vertebrate animals. Most of these bile acids have been known to be generally hydroxylated derivatives of 5.beta.-cholanic acid having 24 carbon atoms.
In human bile, cholic acid, deoxycholic acid, chenodeoxycholic acid, lithocholic acid and the like are contained, but slight differences can be seen in the kind and composition of bile acids depending on the species of animals (for example, there exist species specific bile acids such as ursodeoxycholic acid in the bile of bears and .beta.-muricholic acid in the bile of rats).
These bile acids are essential components absolutely required for absorption of fats or vitamins and control of lipid metabolism in living bodies, and among them, dehydrocholic acid and ursodeoxycholic acid have been frequently used for the purpose of promoting bile secretion, dissolution of gallstone, lipid digestion and absorption, conditioning of intestine, etc.
On the other hand, as for the distribution of bile acids, they are synthesized from cholesterol in the liver and, after being conjugated with glycine or taurine, secreted into the bile and stored and concentrated within the gallbladder, and thereafter released into the duodenum. Bile acids have been known to be absorbed through the ileum after having fulfilled functions such as emulsification (solubilization) of substances insoluble in water in the small intestine, enter the portal vein, be taken up in the liver cells and again secreted into the bile (circulation of intestine-portal vein-liver-bile duct, namely, enterohepatic circulation).
Recently, studies have been made on the derivatives utilizing the unique functions possessed by the bile acids as described above. For example, Ito et al. synthesized compounds in which iminodiacetic acid is bound to the 23-position carboxyl group of naturally occurring bile acids, and reported that they are useful as gallstone dissolving agents on the basis of the finding that they have a remarkable calcium carbonate dissolving activity (see Japanese Patent Laid-Open Publications Nos. 161996/1985 and 163896/1985). However, concerning the derivatives in which N-haloalkylamino acid is bound by the ester bond to the 3-position hydroxyl group of naturally occurring bile acids, they have not even existed themselves as far as we are aware, nor has there been any report up to date about the fact that carcinostatic activity is found in the natural bile acids or their derivatives.